Practice Based Evidence for Treatment of Pregnancy and Anthracycline Cardiomyopathy

Transcription

1 Practice Based Evidence for Treatment of Pregnancy and Anthracycline Cardiomyopathy JEAN-BERNARD DURAND, M.D., FCCP, FACC,FACP,FHFSA,FAHA PROFESSOR OF MEDICINE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER MEDICAL DIRECTOR CARDIOMYOPATHY SERVICES DIRECTOR CARDIOVASCULAR GENETICS RESEARCH CO-CHAIR IRB HOUSTON, TEXAS

2 Jean-Bernard Durand, M.D. Presenter Disclosure Information I will not discuss off label use and/or investigational use in my presentation. I have the following financial relationships to disclose: Funding-NHLBI,NIH,NCI/American Cancer Society Employee of: University of Texas MD Anderson Cancer Center

3 Things to Consider: WHO Death 17 Million-48% CV Diseases 7.6 Million-21%-Cancer Nearly 25 Million Deaths in the combined field 2/3 of all Cancer deaths from Low/Middle income countries Males-US-Prostate Females-Worldwide-Breast 60% of Worlds new cancer cases: Africa, Asia, Central & South America WHO-Projections-2008

4 Common Cancers Treated with Anthracyclines Anthracycline-Based Therapies are still part of treatment in > 50% of all childhood Malignancies Mantle Radiation is also Standard of Care Early and late Presentation (Day 1-20 Years) Sarcoma RhabdomyoSarcoma Lymphoma Leukemia Osteosarcoma Wilms Tumor Breast Cancer (FAC)

5 The Initial Pre-Chemo Consult Patients from age 16 are referred by oncologist to cardiomyopathy service for risk assessment of Anthracycline-based treatment and plan Risk of Left Ventricular Dysfunction prior, during and after pregnancy with prior Anthracycline-based therapy Assessment includes H & P, screening 3D Echocardiogram (Class I) (Strain/BNP/ Troponin are MDACC protocol) Discussion of Risk of Cardiomyopathy (8-16%) up to 20 years after exposure Chemotherapy can lead to infertility/ Fertility Planning

6 Late Mortality Among 5 Year Survivors of Childhood Cancer CCSS Armstrong GT et al. JCO.2009;27: N=20,483

7 Cumulative Incidence at age 45: Cardiovascular Events (grade 3 5) JCO Armstrong et al-2012

8 Differential Diagnosis Cardiomyopathy in Cancer Patients (Diagnosis of Exclusion) Stress Cardiomyopathy Sepsis (Cytokine Release Syndrome) Acute Myocarditis S/P BMT/SCT Transfusion Related Cardiomyopathy (MDS) Anthracycline Tyrosine Kinase Inhibitors (MultiKinase) Thyroid Disease Cardiac Amyloidosis

9 Anthracyclines Doxorubicin Label Adapted from Doxorubicin label.

10 Is From 35 Year-Old Data! 1979: Report by Von Hoff in Ann Int Med Retrospectively reviewed records of 4018 patients who received doxorubicin Definition of doxorubicin-induced CHF: Clinical signs/symptoms of CHF believed to be secondary to doxorubicin by the clinician No routine LVEF assessment!

11 A More Recent Look at the Data Study of three anthracycline trials Significant event: Symptomatic CHF or EF drop >20% or EF drop >10% from normal to below LLN, or EF drop >5% in patient already below LLN Almost identical data to what was seen in adjuvant breast CA studies 7.6% incidence at 240 mg/m 2 Adapted from Swain et al. Cancer. 2003;97:

12 18: , 2012

13 Two different Top2: a and b Doxorubicin poisons both Top2a and Top2b. Proliferating cells express Top2a. However, the adult heart only expresses Top2b. New Hypothesis Doxorubicin-induced cardiotoxicity is mediated by Top2b

14 Top2b deletion prevents doxorubicin-cardiotoxicity

15 Doxorubicin-induced mitochondrial change is Top2b-dependent Control Doxorubicin

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18 Comparison of LVEF at Baseline and After Chemotherapy Data expressed as mean values. Kalay et al. JACC. Dec :

19 Overcome Trial JACC Apr N=90

20 Overcome Trial JACC Apr N=90

21 Limited Time to Start Therapy Journal of American College of Cardiology January 2010

22 MD Anderson Experience with Anthracycline and Pregnancy Retrospective review of 337 patients Pregnant and exposed to Anthracycline therapy with or without Chest Radiation Minimum 10 years follow up (median 20) Control group 80 women w/o Pregnancy, however similar Anthracycline/Radiation Control group- 12 (15%) LVEF<50% Pregnancy group 17 (29%) LVEF<50% JACC-2017, Thompson et al

23 MD Anderson Experience with Anthracycline and Pregnancy 17 (29%) had LVEF <50% 3-Prior to pregnancy 9-During pregnancy 47% recovered 41% Unrecovered 2(11.8% died) Older age time of cancer Dx, had 14% Risk reduction Long time to pregnancy showed increased risk High Dose Anthracycline showed increased risk Pregnancy associated with 2.35 fold increase in LVSD

24 Thompson KA, et al. J Am Col Cardiol, 2017; 69 (5): 594-5

25 Survival of Patients with and without Recovery of LV Function Oliveira GH, et al., Am J Cardiol 113(11):

26 Neurohormonal Activation in Cancer Biology Growth of Tumor Angiotensin II Norepinephrine Angiogenesis, Proliferation,Cell Growth, Undifferentiation Metastasis, Morbidity and Mortality

27 Binding to specific adrenergic receptors, β-blockers inhibit cancer cell migration and metastasis, suggesting a novel targeted therapeutic application in protecting against breast cancer disease progression Powe, D. G. & Entschladen, F. Nature Reviews Clinical Oncology 8, (2011)

28 J Clin Oncol 29;

29 Baseline Hypertensive BC Patients Treated with Beta Blockers Live Longer Oncotarget 2010; 1:

30 Organizations Conclusions Conquer- MD Anderson Cancer Center-2001 Cardiology Oncology Partnership Vanderbilt USA-2004 International Society for Cardioncology Milan, Italy 2009 Brazilian Cardiology Oncology 2009 Sao Paulo, Brazil Canadian Cardioncology 2010 Pan Asia Cardioncology Society-2017

31 Conclusions Little data exist in pregnant and non pregnant population, need to work within organizations for prospective database Beta blockers should be considered prior, during and well after pregnancy. Patients should be managed as high risk and have frequent H & P. Unfortunately, no consensus on when and how frequent LV function should be assessed.

32 Thank you! Twitter- Jean-Bernard

33 COG Guidelines for Cardiac Screening Detailed history yearly EKG for evaluation of QT interval at baseline ECHO or MUGA for evaluation of systolic function at baseline, then periodically.